Nerves exert a control on salamander limb regeneration. The present proposal outlines experiments to explore two major questions on the nature of this neurotrophic phenomenon: 1) What regenerate cellular mechanisms are controlled by the nervous agent? Two studies, already initiated, are described: on changes in phospholipid of regenerate cell membranes after nerve transection, and on nerve-dependent alterations in RNA synthesis. 2) What is the nature of the nervous trophic agent? Preliminary studies show that an extract of nervous tissue can reverse the effect of denervation on protein synthesis. A method of assay for the active principle is presented. Support is also sought to continue studies on the metabolic and trophic interactions between the myelin-Schwann sheath and the axon. The proposed studies are based on our initial findings that electron dense substances are transported through the myelin-Schwann sheath and enter the axon where they are deposited in the agranular axoplasmic reticulum. In this transport Schmidt-Lanterman clefts appear to play an important role. Emphasis will be placed on continued study of the clefts using cinemicrophotographic and EM methods. BIBLIOGRAPHIC REFERENCES: Nordlander, R. and M. Singer, 1976. Synaptoid profiles in regenerating crustacean peripheral nerves. Cell Tissue Res. 166:4, 445-460. Singer, M., C.E. Maier and W.S. McNutt, 1976. Neurotrophic activity of brain extracts on forelimb regeneration in the urodele, Triturus. J. Expt. Zool. 196: 2, 131-150.